Discontinuation of mechanical ventilation is too frequently difficult and frustrating for the patient and the clinician alike. With the view that expeditious withdrawal of mechanical support is often a mirror-image exercise requiring reversal of the factors that led to respiratory failure, we begin with a discussion of the various pathophysiologies of respiratory failure. We then describe an approach emphasizing assessment of respiratory load and neuromuscular function at the bedside, with strategies outlined for diminishing mechanical load while conditioning and strengthening respiratory muscles to the point that spontaneous ventilation can be sustained.